Autocatalytic RNA cleavage in the human β-globin pre-mRNA promotes transcription termination

New evidence indicates that termination of transcription is an important regulatory step, closely related to transcriptional interference 1 and even transcriptional initiation 2 . However, how this occurs is poorly understood. Recently, in vivo analysis of transcriptional termination for the human β-globin gene revealed a new phenomenon—co-transcriptional cleavage (CoTC) 3 . This primary cleavage event within β-globin pre-messenger RNA, downstream of the poly(A) site, is critical for efficient transcriptional termination by RNA polymerase II 3 . Here we show that the CoTC process in the human β-globin gene involves an RNA self-cleaving activity. We characterize the autocatalytic core of the CoTC ribozyme and show its functional role in efficient termination in vivo . The identified core CoTC is highly conserved in the 3′ flanking regions of other primate β-globin genes. Functionally, it resembles the 3′ processive, self-cleaving ribozymes described for the protein-encoding genes from the myxomycetes Didymium iridis and Physarum polycephalum , indicating evolutionary conservation of this molecular process. We predict that regulated autocatalytic cleavage elements within pre-mRNAs may be a general phenomenon and that functionally it may provide the entry point for exonucleases involved in mRNA maturation, turnover and, in particular, transcriptional termination.